Improved Survival of Young Patients With Breast Cancer 40 Years and Younger at Diagnosis

PURPOSE Around 50% of patients with breast cancer in low- or middle-income countries are younger than 50 years, a poor prognostic variable. We report the outcome of patients with breast cancer 40 years and younger. METHODS We reviewed 386 patients with breast cancer 40 years and younger and retrieved demographic, clinicopathologic, treatment-related, disease progression, and survival data from electronic medical records. RESULTS The median age at diagnosis was 36 years, and infiltrating ductal carcinoma was present in 94.3% of patients, infiltrating lobular carcinoma in 1.3%, and ductal carcinoma in situ in 4.4%. Grade 1 disease was present in 8.5% of patients, grade 2 in 35.5%, and grade 3 in 53.4%; 25.1% had human epidermal growth factor receptor 2 (HER2)–positive, 74.6% had hormone receptor (HR)+, and 16.6% had triple-negative breast cancer. Early breast cancer (EBC) constituted 63.6% (stage I, 22.4%; stage II, 41.2%) of patients, whereas 23.2% had stage III, and 13.2% had metastatic disease at diagnosis. Of patients with EBC, 51% had partial mastectomy and 49.0% had total mastectomy. And 77.1% had chemotherapy with or without anti-HER2 therapy. All HR+ patients received adjuvant hormonal therapy. The disease-free survival at 5 years was 72.5% and 55.9% at 10 years. The overall survival (OS) was 89.4% at 5 years and 76% at 10 years. Patients with stages I/II had an OS of 96.0% at 5 years and 87.1% at 10 years. Patients with stage III had an OS of 88.3% at 5 years and 68.7% at 10 years. The OS of patients with stage IV was 64.5% at 5 years and 48.4% at 10 years. CONCLUSION We report survival rates of 89% at 5 years and 76% at 10 years with modern multidisciplinary management. Best results were seen in EBC: OS rates of 96% and 87% at 5 years and 10 years.


INTRODUCTION
Breast cancer is the most common malignancy in women worldwide and is the number one cause of mortality in women. 1 The incidence rate in the United States among White females younger than 40 years was 129 of 100,000, and they constitute ,5% of the total number of breast cancers in the United States. 2 Early-onset breast cancer before age 40 years is generally associated with a worse outcome and more advanced presentations. 2 The tumor biology is, in general, more aggressive, and clinical outcomes are worse in the subgroup of women below age 40 years. 3In the United States and Europe, the median age of women with breast cancer is 63 years at onset, 19% are diagnosed below age 50 years, and only 5% are diagnosed below age 40 years, 2 whereas in Lebanon, the Arab Countries, and most low-or middle-income countries (LMICs), 50% of patients with breast cancer are diagnosed below age 50 years, 4 and 20.8% are below age 40 years. 5A study of 1,320 patients with breast cancer at the American University of Beirut Medical Center (AUBMC) found that younger (younger than 35 years) patients had a worse outcome in multivariate analysis. 6Furthermore, early-onset breast cancer was shown to be an independent risk factor for relapse in a retrospective study of 2,040 patients with consecutive primary invasive breast cancer as younger age at diagnosis remained a significant predictor of recurrence in multivariate analysis (P = .010). 3 The relatively worse prognosis of early-onset breast cancer is due to a multitude of factors. 7Some studies suggest that breast cancer in young women is associated with more estrogen receptor/progesterone receptor (ER/PR) negativity and human epidermal growth factor receptor 2 (HER2) overexpression, 3,8 which could partially explain the worse prognosis since such a pattern of receptor expression confers a worse outcome and survival when compared with luminal A and B when compared with their older counterparts. 3Furthermore, many studies have shown that breast cancer in young women tends to present with more advanced stages than in older patients.The risk of local recurrence of breast cancer was shown to be higher in younger patients in many previous studies. 2][11] We report results from the AUBMC, a primary and tertiary care center in Lebanon.

Patients and Data Collection
We reviewed the list with all the patient's hospital identification number for a sample of patients with breast cancer seen at AUBMC between 2010 and 2018.Oral consent was obtained from all patients included in the study.Using the simple random sampling method, 12 we reviewed available complete survival data of 386 patients to be included in this analysis.After the approval of the institutional review board of AUBMC, we collected information from the medical records of the patients from the hospital's outpatient clinics and inpatient and radiation oncology departments.

Study Variables
Variables were collected using an electronic data collection sheet, which included the following: demographic data, medical history, date of diagnosis, staging, surgical interventions, pathologic characteristics, genetic testing, treatment details, follow-up dates, recurrence details, and morbidity.Demographics included age and sex.Biopsy details included date and type of diagnosis.Pathologic data included information on tumor size, grade, histology, receptor status, and axillary lymph nodes.Hormonal receptors were determined by immunohistochemistry and were considered positive when ER, PR, or both were positive.HER2 was considered positive if +3, equivocal if +2, and negative if +1 or zero.Equivocal results were furthered checked using fluorescence in situ hybridization testing, all according to the ASCO/College of American Pathologists (CAP) guidelines. 13NM staging was used according to American Joint Committee on Cancer eighth edition. 14eatment data included type and duration of neoadjuvant therapy, date of surgery, breast-conserving surgery (BCS)

CONTEXT Key Objective
Has the survival of patients diagnosed below age 40 years with breast cancer improved in clinical practice?Knowledge Generated Application of modern multidisciplinary management produced improved overall survival rates of 76% at 10 years in young patients with breast cancer.Ten-year survival rates of young patients with early breast cancer reached 87%, and patients with locally advanced and metastatic breast cancer reached rates of 68.7% and 48.4%, respectively.Two thirds of breast cancer cases are diagnosed at early stages because of early detection campaigns.Relevance Global availability and access to newer modalities of therapy and medication are essential to improve survival.or mastectomy, number of lymph nodes removed, number of positive lymph nodes, date of axillary lymph node dissection, adjuvant chemotherapy, radiation therapy, and hormonal therapy.Follow-up data included information about local and distant sites of recurrence.Dates and causes of death of deceased patients were recorded.

Statistical Methods
The data were analyzed using statistical package for the social sciences (SPSS) version 25.Frequencies of all the variables in question were calculated according to univariate analysis, including frequencies, and bivariate analysis involving the calculation of two-sided P value using Pearson's chi square test to identify a significant correlation between the variables: median age at diagnosis, stage, grade, type, tumor size, ER and PR status, HER2 receptor status, lymph node (LN) status, surgery date and type, radiation therapy, neoadjuvant and adjuvant chemotherapy, and hormonal therapy.Disease-free survival (DFS) was defined as the time from the date of diagnosis to the date of disease recurrence or last follow-up date for censored patients.OS was defined as the time from the date of diagnosis to the date of last follow-up or date of death.

RESULTS
A total of 386 patients below age 40 years were included (Table 1 Hormonal receptors were positive in 288 patients (74.6% of patients), whereas HER2 was positive in 101 of 355 patients of confirmed HER2 (26.2%).Triple-negative breast cancer (TNBC) was found in 16.6% (64).HER2 testing results were missing in 31 patients.

Management
Neoadjuvant therapy was given to 85 patients (22.0%), adjuvant chemotherapy was given to 213 patients (55.1%), 23 patients (6.0%) had both neoadjuvant and adjuvant treatment, and 21 patients (5.4%) had palliative treatment.Adjuvant radiotherapy was given to 304 patients (78.8%).Adjuvant hormonal therapy was given to 274 patients (71% of the total 386).Although all 288 patients with hormone receptor-positive disease were given hormonal therapy, 14 patients did not complete at least 5 years of adjuvant hormonal therapy.
As for surgery, 51% of patients had a total mastectomy and 49% had BCS, which consisted of a partial mastectomy with radiation therapy.There were 62.5% of patients with stage I and 58.1% of patients with stage II that had BCS.Of 73 patients with stage III, 24.7% had BCS.The majority of patients had adjuvant chemotherapy, and 61.3% of patients who had neoadjuvant treatment underwent mastectomy (52 of 85).
Of patients with stage I breast cancer, 66.2% (57 of 86) had adjuvant chemotherapy, 60.3% of patients with stage II (96 of 159) had adjuvant chemotherapy, and 40.5% of patients with stage III disease (36 of 90) had adjuvant chemotherapy.Of 51 patients with stage IV breast cancer, 8 (15.8%) patients had systemic chemotherapy.Adjuvant hormonal therapy was given to all patients with positive hormonal receptors.
The survival rates in Table 2 were also reflected in the survival function curves (Figs 1 and 2). Figure 1 shows that DFS was best in patients who were stage I at diagnosis and  worst in those who were stage III.Overall survival (OS), however, was best in patients who were stage II at diagnosis and worst in those who were stage IV as shown in Figure 2. Survival by subtype is as follows: for luminal A patients, the 5-year survival was 90.7% and the 10-year survival was 82.6%.For luminal B patients, the 5-year survival was 87.8% and the 10-year survival was 74.2%; for HER2 patients, the 5-year survival was 82.6% and the 10-year survival was 63.0% (Table 3); for TNBC patients, the 5-year survival was 87.8% and the 10-year survival was 80.4%.
OS was better at 5 and 10 years in node-negative disease (93.8% and 83.3%, respectively) compared with node-positive disease (89.4% and 74.3%, respectively; The DFS for patients with stage I breast cancer was 82.3% and 76% at 5 and 10 years, respectively, compared with 73.9% and 40% for patients with stage III at diagnosis.DFS, disease-free survival.node-negative disease (83.1% and 79.8%, respectively) compared with node-positive disease (77.6% and 51%, respectively; Table 4).

Time (years)
The rates in Table 4 are also reflected in Figures 3 and 4, which showed a better OS and DFS in node-negative disease when compared with node-positive disease.

DISCUSSION
In this study, we looked at the outcome of 386 patients below age 40 years who underwent modern chemotherapy, targeted therapy, neoadjuvant/adjuvant therapy, surgery, radiation therapy, and hormonal therapy.Management was performed in Lebanon, which is considered a LMIC.We show that the majority (88.9%) had a grade 2 or 3 tumor (53.4% of patients had a grade 3 breast cancer, and 35.5% grade 2), 74% had positive hormone receptors, 26% had HER2-overexpressive tumors, and 16.6% had TNBC.Of the patients in the study, 22.4% had stage I, 41.2% had stage II, 23.2% had stage III, and 13.2% had stage IV disease at presentation.As for the pathology, the majority of our patients had IDC constituting 94%; DCIS was present in only 4.4%, and ILC in 1.3%.
The patient and tumor characteristics indicate that our cohort of patients has the features that may explain the worse outcome observed in younger patients with breast cancer.However, we report high OS rates of 89.4% at 5 years and 76% at 10 years and OS rates of 93.8% at 5 years and 83.3% at 10 years in patients with node-negative disease and 89.4% at 5 years and 74.3% at 10 years for patients with node-positive disease.These results are very encouraging and translate the advances attributed to the modern therapy with neoadjuvant, adjuvant, surgery, radiation, targeted therapy, and hormonal therapy.We also confirm better results in patients with earlier stages and support awareness and early detection in LMICs as well.As for access to newer therapeutic agents, medications are usually made available in Lebanon after they are approved by the (US) Food and Drug Administration and/or the European Medicinal Agency.Governmental and private sector employees are generally covered under various public health insurance plans including National Social Security Fund and private insurances. 15,16edications that were available at the AUBMC were also available throughout the country for all patients.
Our results indicate that the prognosis and outcome of young women with breast cancer improve with modern multidisciplinary management that includes neoadjuvant/adjuvant therapy, surgery, radiation, targeted therapy, and hormonal therapy according to their tumor characteristics and stage.Newer modalities of treatment have more recently also shown improvement in the outcome and survival of patients with breast cancer.Clinical trials with the new anti-HER2 agents in the neoadjuvant and adjuvant settings and metastatic settings in HER2-positive disease, [17][18][19][20] cyclin-dependent kinase 4/6 inhibitors in the metastatic and adjuvant setting in hormone receptor-positive disease, 21 immunotherapy in the metastatic  and neoadjuvant setting in TNBC, 22,23 and poly (ADP-ribose) polymerase inhibitors in patients with germline BRCA mutations 24 have shown improvement in survival of patients with breast cancer.
In conclusion, we report high survival rates in young patients diagnosed below age 40 years with breast cancer treated with modern multidisciplinary management.We report survival rates of 89% at 5 years and 76% at 10 years.Best results are seen in patients with early breast cancer; patients with stages I and II had an OS of 96.0% at 5 years and 87.1% at 10 years, whereas patients with stage III had an OS of 77.0% at 5 years and 66.0% at 10 years.
Modern multidisciplinary management, guided by biology and modern therapies, can help us remove the stigma of poor prognosis in young women with breast cancer.Our data, coming from a LMIC, show that improvement is achievable everywhere when resources are available and treatment is accessible.

1 FIG 2 .
FIG 2. Survival by stage, OS (n = 323).The OS was 100% at 5 years and 95.5% at 10 years for patients with stage II disease at diagnosis compared with 65.5% at 5 years and 48.4% at 10 years for patients with stage IV at diagnosis.OS, overall survival.
). Age ranged between 19 and 40 years.The median age was 36 years.

TABLE 2 .
DFS and OS by Stage at Diagnosis

TABLE 4 .
DFS and OS by Node Status